Continuing Education Activity

Neuromuscular blocking agents are commonly used to paralyze patients requiring intubation whether in an emergency as a life-saving intervention or as a scheduled surgery and procedure. The indications for intubation during an emergency can be divided into 3 categories: failure to maintain or protect the airway, failure to adequately ventilate or oxygenate, and anticipation of a decline in clinical status. This activity will highlight the mechanism of action, adverse event profile, off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions of these agents, pertinent for members of the interprofessional team in the treatment of patients where a neuromuscular blockade is needed.

Objectives:

• Identify the two basic mechanisms of action of depolarizing neuromuscular blockade drugs.
• Explain the indications where depolarizing neuromuscular blockade agents are appropriate.
• Outline the adverse events and monitoring necessary when using depolarizing neuromuscular blocking agents.
• Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients undergoing procedures where depolarizing neuromuscular blocking agents are used.

Indications

Neuromuscular blocking agents are commonly used to paralyze patients requiring intubation whether in an emergency as a life-saving intervention or as a scheduled surgery and procedure. The indications for intubation during an emergency can be divided into 3 categories: failure to maintain or protect the airway, failure to adequately ventilate or oxygenate, and anticipation of a decline in clinical status. 

Pharmacologic paralysis is a vital aspect of rapid sequence intubation (RSI), improves visualization of the glottic anatomy, and prevents vomiting during intubation attempts. Importantly, the conjunctive use of induction agents is vital to RSI to reduce the sympathetic reflexes, improve intubating conditions, and avoid the unwarranted effect of paralyzing a conscious patient.

The most well-known depolarizing neuromuscular blocking agent is succinylcholine. It is the only such drug used clinically and is considered by many the drug of choice for emergency department RSI, although this is controversial. It provides the fastest of optimal conditions during intubation of critically ill patients.

Mechanism of Action

There are 2 types of neuromuscular blocking agents that work at the neuromuscular junction: depolarizing and non-depolarizing. Depolarizing muscle relaxants act as acetylcholine (ACh) receptor agonists by binding to the ACh receptors of the motor endplate and generating an action potential. However, they are resistant to and not metabolized by acetylcholinesterase, leading to persistent depolarization of the muscle fibers, resulting in the patient's well-recognized muscle fasciculations and paralysis. This is in contrast to non-depolarizing muscle relaxants, which act as competitive antagonists. They bind (ACh) receptors but do not produce an action potential. Thus, they prevent ACh from binding, and as a result, neural endplate potentials do not develop.[1][2]

After a depolarizing agent binds to the motor endplate receptor, the agent remains bound, and thus the endplate cannot repolarize. This is also known as a phase I block. It is during this depolarizing phase that transient muscle fasciculation occurs. After adequate depolarization, phase II (desensitizing phase) sets in, and the muscles are no longer receptive to acetylcholine released by the motor neurons. It is at this point that the depolarizing agent has fully achieved paralysis.[2]

It is also important to recognize that these muscle relaxants target not only nicotinic receptors but also muscarinic receptors.[3] The classical depolarizing blocking drug is succinylcholine. It has a rapid onset (30 seconds) and a short duration of action (approximately 6 minutes) because of the degradation by various cholinesterases.[2]

Adverse Effects

Since these drugs cause paralysis of the diaphragm, mechanical ventilation should be at hand to provide respiratory support. In addition, these drugs may produce cardiovascular effects, including dysrhythmias, since they have effects on muscarinic receptors.[3] When nicotinic receptors of the autonomic ganglia or adrenal medulla are blocked, these drugs cause autonomic symptoms. In addition, neuromuscular blockers result in a histamine release leading to hypotension, flushing, and tachycardia.[3] The depolarizing effect on the muscle fibers may momentarily release a large amount of potassium. This places the patient at risk for life-threatening complications such as hyperkalemia and cardiac arrhythmias.[2][3]

More Adverse Effects[2][3]

• Muscle fasciculation, which may result in postoperative pain
• Jaw rigidity
• Apnea
• Respiratory depression
• Bradycardia
• Hypotension
• Sinus tachycardia
• Increased IOP
• Excessive salivation
• Hypersensitivity reactions
• Malignant hyperthermia
• Myoglobinuria/myoglobinemia

Contraindications

As mentioned above, depolarizing muscle agents bind to all acetylcholine receptors of the autonomic nervous system, and when targeting cardiac muscarinic receptors, patients may develop bradycardia, especially in repeat doses. There is a relative contraindication in a patient with bradycardia. In addition, the defasciculations result in a large amount of potassium release and oxygen depletion.[3]

Depolarizing muscle agents are contraindicated in cases of neurologic injuries, such as a cerebral vascular accident or spinal cord injury or severe tissue injury, including trauma or burns. This results from post-synaptic receptor up-regulation that typically occurs within three to five days. These injuries place the patient at risk for life-threatening hyperkalemia. Of note, the risk of hyperkalemia is not associated with decreased potassium clearance; however, attention should be given to those who have chronically elevated potassium levels, such as renal failure patients.[3]

Depolarizing agents are absolutely contraindicated in patients with degenerative neuromuscular disorders or a history of malignant hyperthermia. Undiagnosed children with skeletal muscle myopathy, such as Duchenne's muscular dystrophy, are at risk for rhabdomyolysis with hyperkalemia.[3][4] This is subsequently followed by ventricular dysrhythmias, cardiac arrest, and death. It occurs soon after administration and requires immediate treatment of hyperkalemia. In children, it is reserved for emergency intubation or in instances when securing the airway is immediately necessary.

Other Contraindications[2][3]

• Hypersensitivity to drug
• Malignant hyperthermia
• Lack of ventilatory support
• Ocular surgery, Penetrating eye injuries, Closed-angle glaucoma 
• Disorders of plasma pseudocholinesterase - Patients with atypical or deficient pseudocholinesterase will have prolonged paralysis
• Myopathies associated with elevated serum creatine kinase
• Extensive denervation of skeletal muscle or upper motor neuron injury

Monitoring

The proper precautions are necessary because of the potential severity of these agents. The immediate availability of appropriate emergency treatment is unquestionable. These agents should be administered by trained personnel with a facility equipped to monitor, assist, and control respiration.

Toxicity

Malignant hyperthermia is a life-threatening clinical syndrome of hypermetabolism involving the skeletal muscle. It is triggered in susceptible individuals primarily by inhalational anesthetic agents and the muscle relaxant succinylcholine, although other drugs have also been considered potential triggers. It is not an allergy but an inherited disorder. A typical presentation involves tachycardia, dysrhythmias, rigidity, rapidly increasing temperature, hyperkalemia, sympathetic hyperactivity, disseminated intravascular coagulopathy (DIC), and multi-organ failure.[5] Dantrolene is the primary drug used for the treatment and prevention of malignant hyperthermia.[6]

Enhancing Healthcare Team Outcomes

Several controversies persist regarding RSI. The most prominent debate centers on the use of rocuronium versus succinylcholine for standard RSI paralysis. Advocates of rocuronium cite its lack of contraindications and avoidance of depolarization in the middle of an intubation attempt. Advocates for succinylcholine argue for its rapid onset and rapid recovery time thought to be potentially helpful in a critically ill patient who is difficult to intubate and oxygenate. One of the main differences between these two types of neuromuscular-blocking drugs is in their reversal and pharmacokinetics. Acetylcholinesterase inhibitor drugs reverse non-depolarizing blockers since they are competitive antagonists at the ACh receptor site and thus, reverse by increasing in ACh. On the other hand, the depolarizing blockers are more resistant to acetylcholinesterase resulting in a prolonged effect under the administration of acetylcholinesterase inhibitors. The argument is mostly academic. Both agents are excellent, and when dosed properly, result in comparable intubating conditions.[7][8]

When using depolarizing neuromuscular blockade drugs, it is important to have an interprofessional team involved, including clinicians and specialists, anesthesiologists and/or nurse anesthetists, pharmacists, nurses, and EMT personnel. These individual disciplines need to function as a cohesive unit and exercise open communication so the patient can receive the necessary anesthesia and other procedures and achieve optimal outcomes. [Level 5]